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European Journal of Pharmaceutics and... Nov 2023Tissue-type plasminogen activator (tPA) is the gold standard for emergency treatment of ischemic stroke, which is the third leading cause of death worldwide. Major...
Tissue-type plasminogen activator (tPA) is the gold standard for emergency treatment of ischemic stroke, which is the third leading cause of death worldwide. Major challenges of tPA therapy are its rapid elimination by plasminogen activator inhibitor-1 (PAI-1) and hepatic clearance, leading to the use of high doses and consequent serious side effects, including internal bleeding, swelling and low blood pressure. In this regard, we developed three polyethylene glycol (PEG)ylated tPA bioconjugates based on the recombinant human tPA drug Alteplase using site-specific conjugation strategies. The first bioconjugate with PEGylation at the N-terminus of tPA performed by reductive alkylation showed a reduced proteolytic activity of 68 % compared to wild type tPA. PEGylation at the single-free cysteine of tPA with linear and branched PEG revealed similar proteolytic activities as the wild-type protein. Moreover, both bioconjugates with PEG-cysteine-modification showed 2-fold slower inhibition kinetics by PAI-1. All bioconjugates increased in hydrodynamic size as a critical requirement for half-life extension.
Topics: Humans; Tissue Plasminogen Activator; Plasminogen Activator Inhibitor 1; Cysteine
PubMed: 37783360
DOI: 10.1016/j.ejpb.2023.09.017 -
Advanced Science (Weinheim,... Jun 2024Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) is the primary treatment for ischemic stroke. However, rtPA treatment can substantially...
Intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) is the primary treatment for ischemic stroke. However, rtPA treatment can substantially increase blood-brain barrier (BBB) permeability and susceptibility to hemorrhagic transformation. Herein, the mechanism underlying the side effects of rtPA treatment is investigated and demonstrated that ferroptosis plays an important role. The ferroptosis inhibitor, liproxstatin-1 (Lip) is proposed to alleviate the side effects. A well-designed macrocyclic carrier, glucose-modified azocalix[4]arene (GluAC4A), is prepared to deliver Lip to the ischemic site. GluAC4A bound tightly to Lip and markedly improved its solubility. Glucose, modified at the upper rim of GluAC4A, imparts BBB targeting to the drug delivery system owing to the presence of glucose transporter 1 on the BBB surface. The responsiveness of GluAC4A to hypoxia due to the presence of azo groups enabled the targeted release of Lip at the ischemic site. GluAC4A successfully improved drug accumulation in the brain, and Lip@GluAC4A significantly reduced ferroptosis, BBB leakage, and neurological deficits induced by rtPA in vivo. These findings deepen the understanding of the side effects of rtPA treatment and provide a novel strategy for their effective mitigation, which is of great significance for the treatment and prognosis of patients with ischemic stroke.
Topics: Animals; Ferroptosis; Mice; Ischemic Stroke; Disease Models, Animal; Tissue Plasminogen Activator; Drug Delivery Systems; Blood-Brain Barrier; Male; Quinoxalines; Spiro Compounds
PubMed: 38647405
DOI: 10.1002/advs.202309517 -
International Journal of Molecular... Jul 2023Macrophage infiltration and accumulation is a hallmark of chronic kidney disease. Tissue plasminogen activator (tPA) is a serine protease regulating the homeostasis of... (Review)
Review
Macrophage infiltration and accumulation is a hallmark of chronic kidney disease. Tissue plasminogen activator (tPA) is a serine protease regulating the homeostasis of blood coagulation, fibrinolysis, and matrix degradation, and has been shown to act as a cytokine to trigger various receptor-mediated intracellular signal pathways, modulating macrophage function in response to kidney injury. In this review, we discuss the current understanding of tPA-modulated macrophage function and underlying signaling mechanisms during kidney fibrosis and inflammation.
Topics: Mice; Animals; Tissue Plasminogen Activator; Signal Transduction; Kidney Diseases; Macrophages; Kidney
PubMed: 37446244
DOI: 10.3390/ijms241311067 -
JCI Insight Mar 2024Joint injury is associated with risk for development of osteoarthritis (OA). Increasing evidence suggests that activation of fibrinolysis is involved in OA pathogenesis....
Joint injury is associated with risk for development of osteoarthritis (OA). Increasing evidence suggests that activation of fibrinolysis is involved in OA pathogenesis. However, the role of the fibrinolytic pathway is not well understood. Here, we showed that the fibrinolytic pathway, which includes plasminogen/plasmin, tissue plasminogen activator, urokinase plasminogen activator (uPA), and the uPA receptor (uPAR), was dysregulated in human OA joints. Pharmacological inhibition of plasmin attenuated OA progression after a destabilization of the medial meniscus in a mouse model whereas genetic deficiency of plasmin activator inhibitor, or injection of plasmin, exacerbated OA. We detected increased uptake of uPA/uPAR in mouse OA joints by microPET/CT imaging. In vitro studies identified that plasmin promotes OA development through multiple mechanisms, including the degradation of lubricin and cartilage proteoglycans and induction of inflammatory and degradative mediators. We showed that uPA and uPAR produced inflammatory and degradative mediators by activating the PI3K, 3'-phosphoinositide-dependent kinase-1, AKT, and ERK signaling cascades and activated matrix metalloproteinases to degrade proteoglycan. Together, we demonstrated that fibrinolysis contributes to the development of OA through multiple mechanisms and suggested that therapeutic targeting of the fibrinolysis pathway can prevent or slow development of OA.
Topics: Animals; Mice; Humans; Fibrinolysin; Osteoarthritis; Fibrinolysis; Urokinase-Type Plasminogen Activator; Receptors, Urokinase Plasminogen Activator; Disease Models, Animal; Male; Female; Mice, Inbred C57BL; Plasminogen; Signal Transduction; Mice, Knockout
PubMed: 38502232
DOI: 10.1172/jci.insight.173603 -
Retina (Philadelphia, Pa.) Nov 2023To investigate factors associated with 3-month or 1-year best-corrected visual acuity (BCVA) after vitrectomy with subretinal tissue plasminogen activator injection for...
PURPOSE
To investigate factors associated with 3-month or 1-year best-corrected visual acuity (BCVA) after vitrectomy with subretinal tissue plasminogen activator injection for submacular hemorrhage (SMH) and to identify the predictors of early displacement.
METHODS
This prospective cohort study included consecutive eyes with SMH complicating neovascular age-related macular degeneration or retinal macroaneurysm that underwent vitrectomy with subretinal tissue plasminogen activator injection and were followed up for at least 3 months. Parameters that correlated with 3-month BCVA, 1-year BCVA, and 2-week displacement grade (0-3) were identified.
RESULTS
Twenty-nine eyes of 29 patients (73.1 ± 8.4 years; neovascular age-related macular degeneration, 25 eyes) were included. Logarithm of the minimum angle of resolution BCVA improved 3 months after the surgery (baseline, 0.76 [20/115] ± 0.35; 3-month, 0.51 [20/65] ± 0.32; P = 0.006). In multivariable analyses, 1-year logarithm of the minimum angle of resolution BCVA correlated with age ( P = 0.007, β = 0.39) and SMH recurrence within 1 year after surgery ( P < 0.001, β = 0.65). Two-week displacement grade correlated with the contrast-to-noise ratio of SMH ( P = 0.001, β = -0.54). Macular hole occurred in three eyes (10%) with small SMH size and was closed in all eyes via additional vitrectomy with an inverted internal limiting membrane flap technique.
CONCLUSION
The recurrence of SMH negatively affected the 1-year visual outcome after vitrectomy with subretinal tissue plasminogen activator injection for SMH. The contrast-to-noise ratio was a useful predictor of early SMH displacement, but not of 1-year BCVA. Further research is necessary to determine the optimal treatment to prevent SMH recurrence.
Topics: Humans; Infant; Tissue Plasminogen Activator; Fibrinolytic Agents; Vitrectomy; Prospective Studies; Treatment Outcome; Follow-Up Studies; Retinal Hemorrhage; Macular Degeneration; Retrospective Studies
PubMed: 37490778
DOI: 10.1097/IAE.0000000000003885 -
BioRxiv : the Preprint Server For... Sep 2023Pulmonary arterial hypertension (PAH) is a progressive and potentially a rapidly fatal disease characterized by vasoconstriction and remodeling of small pulmonary...
Pulmonary arterial hypertension (PAH) is a progressive and potentially a rapidly fatal disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PA) leading to increased pulmonary vascular resistance and right heart failure. Central to the remodeling process is a switch of the smooth muscle cells in small PAs (PASMC) to a proliferative, apoptosis-resistant phenotype. There is reason to suspect that the plasminogen activator system may play an important role in the remodeling program in PAH based on its roles in vascular post-injury restenosis, fibrosis, angiogenesis and tumorigenesis. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of the plasminogen activators - urokinase-type and tissue-type (uPA and tPA, respectively). Immunohisto- chemical and immunoblot analyses revealed that PAI-1 was deficient in smooth muscle areas of small remodeled PAs and early-passage PASMC from subjects with PAH compared to non-PAH controls. male and female mice developed spontaneous pulmonary vascular remodeling and pulmonary hypertension (PH) as evidenced by significant increase in PA medial thickness, systolic right ventricular pressure, and right ventricular hypertrophy. Lastly, the uPA inhibitors upamostat (WX-671) and amiloride analog BB2-30F down-regulated mTORC1 and SMAD3, restored PAI-1 levels, reduced proliferation, and induced apoptosis in human PAH PASMC. We examined the effect of inhibition of uPA catalytic activity by BB2-30F on the development of SU5416/Hypoxia (SuHx)-induced PH in mice. Vehicletreated SuHx-exposed mice had up-regulated mTORC1 in small PAs, developed pulmonary vascular remodeling and PH, as evidenced by significant increase of PA MT, sRVP, RV hypertrophy, and a significant decrease in the pulmonary artery acceleration time/pulmonary ejection time (PAAT/PET) ratio compared to age- and sex-matched normoxia controls, whereas BB2-30F-treated group was protected from all these pathological changes. Taken together, our data strongly suggest that PAI-1 down- regulation in PASMC from human PAH lungs promotes PASMC hyper-proliferation, remodeling, and spontaneous PH due to unopposed uPA activation. Further studies are needed to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate the progression and/or reverse pulmonary vascular remodeling and PH.
PubMed: 37790328
DOI: 10.1101/2023.09.21.558893 -
JAMA Network Open Jul 2023Recombinant human prourokinase (rhPro-UK) is a thrombolytic agent that has shown promising findings in a phase 2 clinical trial in patients with acute ischemic stroke... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Recombinant human prourokinase (rhPro-UK) is a thrombolytic agent that has shown promising findings in a phase 2 clinical trial in patients with acute ischemic stroke (AIS).
OBJECTIVE
To evaluate the efficacy and safety of rhPro-UK thrombolysis within 4.5 hours of symptom onset in patients with AIS.
DESIGN, SETTING, AND PARTICIPANTS
This randomized, alteplase-controlled, open-label, phase 3 clinical trial was conducted from May 2018 to May 2020 at 35 medical centers in China. A total of 684 patients were screened and 674 patients were enrolled. Included patients were aged 18 to 80 years with a diagnosis of AIS and received treatment within 4.5 hours of stroke onset. Data were analyzed from June to October 2020.
INTERVENTIONS
Eligible patients were randomly assigned (1:1) to receive intravenous rhPro-UK or alteplase.
MAIN OUTCOMES AND MEASURES
The primary objective was to assess whether rhPro-UK was noninferior to alteplase. The noninferiority margin was a between-group difference of less than 10%. The primary outcome was a modified Rankin Scale score of 0 to 1 at 90 days.
RESULTS
Among 663 patients in the modified intention-to-treat population (mean [SD] age, 61.00 [10.20] years; 161 females [24.3%]), there were 330 patients in the rhPro-UK group and 333 patients in the alteplase group. The median (IQR) baseline National Institutes of Health Stroke Scale score was 6.00 (5.00-9.00). There were 23 deaths, and 619 patients (93.4%) completed the 3-month follow-up. The primary outcome occurred in 215 patients (65.2%) in the rhPro-UK group and 214 patients (64.3%) in the alteplase group (risk difference, 0.89; 95.4% CI, -6.52 to 8.29). Symptomatic intracerebral hemorrhage occurred in 5 patients (1.5%) in the rhPro-UK group and 6 patients (1.8%) in the alteplase group (P > .99). Systemic bleeding within 90 days occurred more frequently in the alteplase group (141 patients [42.2%]) than the rhPro-UK group (85 patients [25.8%]) (P < .001). By 90 days, 5 thrombolysis-related deaths each had occurred in the rhPro-UK group (1.5%) and alteplase group (1.5%) (P > .99).
CONCLUSIONS AND RELEVANCE
This study found that intravenous rhPro-UK within 4.5 hours of AIS onset was noninferior to alteplase. The rhPro-UK group showed a similar rate of symptomatic ICH but fewer cases of systemic bleeding than the alteplase group.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03541668.
Topics: United States; Female; Humans; Middle Aged; Ischemic Stroke; Tissue Plasminogen Activator; Stroke; Fibrinolytic Agents; Cerebral Hemorrhage
PubMed: 37490291
DOI: 10.1001/jamanetworkopen.2023.25415 -
Neurological Sciences : Official... Feb 2024A 78-year-old woman without past relevant medical history presented to the emergency department for acute transient dysarthria. NIHSS was 0/42. Neurological examination...
A 78-year-old woman without past relevant medical history presented to the emergency department for acute transient dysarthria. NIHSS was 0/42. Neurological examination revealed chorea-like movements over the left limbs, especially the foot. No other neurological signs were present. CT perfusion showed right cortical hypoperfusion due to right M2 occlusion, basal-ganglia perfusion was normal. Brain MRI revealed a small focus of restricted diffusion in the right insula, sparing basal ganglia. Based on the neuroimaging features and clinical correlation, despite the NIHSS score, we decided to treat the patient with alteplase, after iv-thrombolysis hyperkinetic movements ceased completely. Brain-MRI performed 72 h after symptom onset confirmed a confined insular ischemic lesion without the involvement of deep gray matter structures. Hyperkinetic movement disorders, such as hemichorea hemiballismus, are rare presentations of stroke, basal ganglia are mainly involved even if the insular cortex has been described too. Clinical decision on whether to treat ischemic stroke does not include movement disorders. Our case underscores NIHSS limitations in clinical practice.
Topics: Female; Humans; Aged; Stroke; Chorea; Dyskinesias; Movement Disorders; Tissue Plasminogen Activator
PubMed: 37828390
DOI: 10.1007/s10072-023-07112-0 -
ESC Heart Failure Aug 2023We sought to investigate the relationship between circulating tissue plasminogen activator (t-PA) level and long-term outcomes in stable coronary artery disease patients...
AIMS
We sought to investigate the relationship between circulating tissue plasminogen activator (t-PA) level and long-term outcomes in stable coronary artery disease patients with or without aortic valve sclerosis (AVSc).
METHODS AND RESULTS
Serum levels of t-PA were determined in 347 consecutive stable angina patients with (n = 183) or without (n = 164) AVSc. Outcomes were prospectively recorded as planned clinic evaluations every 6 months up to 7 years. The primary endpoint was a composite of cardiovascular death and rehospitalization due to heart failure. The secondary endpoint included all-cause mortality, cardiovascular death, and rehospitalization due to heart failure. Serum t-PA was significantly higher in AVSc than in non-AVSc patients (2131.22 pg/mL vs. 1495.85 pg/mL, P < 0.001). For patients with AVSc, those with t-PA level above the median (>1840.68 pg/mL) were more likely to meet the primary and secondary endpoints (all P < 0.001). After adjusting for potential confounding factors, serum t-PA level remained significantly predictive for each endpoint in the Cox proportional hazard models. The prognostic value of t-PA was good, with an AUC-ROC of 0.753 (P < 0.001). The combination of t-PA with traditional risk factors improved the risk reclassification of AVSc patients, with a net reclassification index of 0.857 and an integrated discrimination improvement of 0.217 (all P < 0.001). However, for patients without AVSc, both primary and secondary endpoints were similar, irrespective of t-PA levels.
CONCLUSIONS
Elevated circulating t-PA confers an increased risk for poor long-term clinical outcomes in stable coronary artery disease patients with AVSc.
Topics: Humans; Coronary Artery Disease; Tissue Plasminogen Activator; Prognosis; Aortic Valve; Sclerosis; Heart Failure
PubMed: 37308095
DOI: 10.1002/ehf2.14420 -
Seminars in Thrombosis and Hemostasis Jul 2024Fibrinolytic agents catalyze the conversion of the inactive proenzyme plasminogen into the active protease plasmin, degrading fibrin within the thrombus and recanalizing... (Review)
Review
Fibrinolytic agents catalyze the conversion of the inactive proenzyme plasminogen into the active protease plasmin, degrading fibrin within the thrombus and recanalizing occluded vessels. The history of these medications dates to the discovery of the first fibrinolytic compound, streptokinase, from bacterial cultures in 1933. Over time, researchers identified two other plasminogen activators in human samples, namely urokinase and tissue plasminogen activator (tPA). Subsequently, tPA was cloned using recombinant DNA methods to produce alteplase. Several additional derivatives of tPA, such as tenecteplase and reteplase, were developed to extend the plasma half-life of tPA. Over the past decades, fibrinolytic medications have been widely used to manage patients with venous and arterial thromboembolic events. Currently, alteplase is approved by the U.S. Food and Drug Administration (FDA) for use in patients with pulmonary embolism with hemodynamic compromise, ST-segment elevation myocardial infarction (STEMI), acute ischemic stroke, and central venous access device occlusion. Reteplase and tenecteplase have also received FDA approval for treating patients with STEMI. This review provides an overview of the historical background related to fibrinolytic agents and briefly summarizes their approved indications across various thromboembolic diseases.
Topics: Humans; Fibrinolytic Agents; Thromboembolism; History, 20th Century
PubMed: 38428841
DOI: 10.1055/s-0044-1781451